Operator-controlled scanning laser procedure designed for large-area epithelium removal

ABSTRACT

Systems and methods for removing an epithelial layer disposed over a stromal layer in a cornea irradiate a region of the epithelial layer with a pulsed beam of ablative radiation. The ablative radiation is scanned to vary the location of the beam within the region in accordance with a pulse sequence. The pulse sequence is arranged to enhance optical feedback based on a tissue fluorescence of the epithelial layer. The penetration of the epithelial layer is detected in response to the optical feedback. The use of scanning with the pulse sequence arranged to enhance optical feedback allows large areas of the epithelium to be ablated such that an operator can detect penetration of the epithelial layer.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit under 35 USC 119(e) of U.S.Provisional Application No. 60/865,342 filed Nov. 10, 2006, entitled“OPERATOR CONTROLLED SCANNING LASER PROCEDURE DESIGNED FOR LARGE-AREAEPITHELIAL REMOVAL,” the full disclosure of which is incorporated hereinby reference.

BACKGROUND OF THE INVENTION

The present invention is generally related to correcting optical errorsof light refracted by eyes. In exemplary embodiments, the inventionprovides devices, systems, and methods for correction of optical errorsof eyes, and is particularly well suited for the treatment of eyesduring photorefractive keratectomy (PRK) and the like.

Known laser eye surgery procedures generally employ an ultraviolet orinfrared laser to remove a microscopic layer of stromal tissue from thecornea of the eye. The laser typically removes a selected shape of thecorneal tissue, often to correct refractive errors of the eye.Ultraviolet laser ablation results in photodecomposition of the cornealtissue, but generally does not cause significant thermal damage toadjacent and underlying tissues of the eye. The irradiated molecules arebroken into smaller volatile fragments photo-chemically, directlybreaking the intermolecular bonds.

Laser ablation procedures can remove the targeted stroma of the corneato change the cornea's contour for varying purposes, such as forcorrecting myopia, hyperopia, astigmatism, and the like. Control overthe distribution of ablation energy across the cornea may be provided bya variety of systems and methods, including the use of ablatable masks,fixed and moveable apertures, controlled scanning systems, eye movementtracking mechanisms, and the like. In known systems, the laser beamoften comprises a series of discrete pulses of laser light energy, withthe total shape and amount of tissue removed being determined by theshape, size, location, and/or number of laser energy pulses impinging onthe cornea. A variety of algorithms may be used to calculate the patternof laser pulses used to reshape the cornea so as to correct a refractiveerror of the eye. Known systems make use of a variety of forms of lasersand/or laser energy to effect the correction, including infrared lasers,ultraviolet lasers, femtosecond lasers, wavelength multipliedsolid-state lasers, and the like. The lasers of these laser systemstypically deliver a series of laser beam pulses during a treatment.

Known corneal correction treatment methods have generally beensuccessful in correcting standard vision errors, such as myopia,hyperopia, astigmatism, and the like. By customizing an ablation patternbased on wavefront measurements, it may be possible to correct minoraberrations so as to reliably and repeatedly provide visual acuitygreater than 20/20. Such detailed corrections will benefit from anextremely accurate ablation of tissue.

With laser ablation procedures, the epithelium is generally removed sothat the permanent optical correction can be ablated into the stroma.With PRK the epithelium is removed to expose Bowman's membrane.Epithelial removal has been accomplished mechanically and with laserablation of the epithelial layer. Mechanical removal of the epitheliallayer can be accomplished with mechanical scraping of the epithelialtissue layer to expose Bowman's membrane. Another mechanical approach isto remove the epithelium with a brush. With Laser-AssistedSub-Epithelial Keratectomy (LASEK), the epithelial layer is removed fromthe cornea as a sheet so that the layer can be replaced following theablation of stromal tissue. Although these mechanical methods ofepithelial removal have been successful clinically, mechanical removalof the epithelium takes time and can be perceived by the patients asinvasive because the surgeon will touch the front surface of the eyewith surgical instruments. Even though topical anesthesia is oftenapplied to the cornea so that the patient cannot feel the surgeontouching his or her cornea, the patient can become nervous while thesurgeon touches the front surface of the eye with the instruments,possibly delaying the procedure.

Laser ablation of the epithelium, also referred to as trans-epithelialablation, can be less invasive and faster than mechanical approaches toremoval of the epithelium. However, work in connection with the presentinvention suggests that the known methodologies for laser ablation ofthe epithelium may be less than ideal. Thus, a surgeon will oftenmechanically scrape the epithelium after laser removal of the epitheliumto ensure that no residual epithelial debris remains before ablatingstromal tissue.

In light of the above, it would be desirable to provide real-timemonitoring of trans-epithelial ablations over large areas of the corneawhile avoiding at least some of the limitations of known systems.

BRIEF SUMMARY OF THE INVENTION

Embodiments of the present invention provide improved devices, systems,and methods for laser treatment, for example laser treatment of eyes.More specifically, embodiments of the present invention can enhance theaccuracy and efficacy of laser eye surgical procedures with improvedremoval of the epithelium, for example the corneal epithelium. Thisimproved removal of the corneal epithelium can improve refractivesurgical procedures, for example PRK, and can be useful for thetherapeutic removal of corneal haze. While the system and methods of thepresent invention are described primarily in the context of a laser eyesurgery system for treating the cornea of the eye, it should beunderstood that the techniques described herein may be adapted for usein many additional ablation procedures.

Many embodiments use a scanning laser beam that ablates an area largerthan the beam and induces fluorescence of the ablated tissue layer, forexample the corneal epithelium. A sequence of pulses of the beam isarranged to enhance optical feedback based on the tissue fluorescence sothat areas of the epithelium larger than the beam can be ablated andtissue penetration detected. The size and position of the pulse sequencecan be arranged to overlap at least some the scanning pulses on a regionsmaller than the ablation, for example a central region, so thatpenetration of the epithelium can be detected by viewing the region.Hence, enhanced optical feedback encompasses scanning pulses with a sizeand position arranged to ablate an area larger than the beam and overlapthe pulses on a region, or portion, of the ablated area so thatpenetration of the epithelium can be detected by viewing the region. Inmany embodiments an operator may view the region and stop the ablationin response to the enhanced optical feedback, and in some embodimentsand energy detector, such as a CCD camera, may view the region ablatedpulse sequence arranged to enhance optical feedback.

In a first aspect, embodiments provide a method for removing anepithelial layer disposed over a stromal layer in a cornea. A region ofthe epithelial layer is irradiated with a pulsed beam of ablativeradiation. The ablative radiation is scanned to vary the location of thebeam within the region in accordance with a pulse sequence. The pulsesequence is arranged to enhance optical feedback based on a tissuefluorescence of the epithelial layer. The penetration of the epitheliallayer is detected in response to the optical feedback.

In many embodiments, the pulse sequence is sorted to enhance the opticalfeedback. Stromal tissue can be ablated with an optical correction inresponse the penetration of the epithelial layer.

In many embodiments, the epithelial layer is ablated to a first depthand an additional sub-layer of epithelial tissue is ablated to a seconddepth in response to the optical feedback.

In specific embodiments, the size of the laser beam is constant whilethe region is irradiated until the penetration of the epithelium isdetected.

In another aspect, embodiments provide a method for removing anepithelial layer disposed over a stromal layer in a cornea. A region ofthe epithelial layer is irradiated with laser beam pulses of ablativeradiation. The ablative radiation is scanned to vary the location of thebeam pulses within the region. The beam is adjusted to at least onesmaller beam size and at least one larger beam size while the beam ispulsed and scanned over the region in accordance with a pulse sequencearranged to enhance optical feedback. The penetration of the epitheliallayer is detected based on tissue fluorescence from the larger sizedbeam.

In many embodiments, the irradiated region has a central region and anouter peripheral region. The adjustably sized beam can be sized andscanned so that several larger sized pulses comprise marker pulses thatoverlap, for example in the central region, such that the penetration ofthe epithelium is detected based on a decrease in fluorescence of thecentral region from the marker pulses.

In some embodiments, each of the marker pulses covers the central regionto provide a measurement signal from the central region. In specificembodiments, the distance across the central region is about 3 mm andeach marker pulse is at least about 3.5 mm across so that each markerpulse overlaps and covers the central region. The marker pulses thatcover the central region may be delivered at a rate of at least about 1Hertz to detect penetration of the epithelium.

In many embodiments, the larger beam size has a distance across of atleast about 3.5 mm and the smaller beam size has a distance across of nomore than about 2.5 mm. In specific embodiments, the adjustably sizedbeam is circular and the distance across comprises a diameter.

In many embodiments, the distance across the region is at least about 8mm, and pulses of the larger beam size can comprise at least about 10%of a total number of pulses delivered before the penetration isdetected.

In many embodiments, the penetration of the epithelium is detected by anoperator based on the visible fluorescence of the epithelial layerirradiated with the large sized pulse.

In some embodiments, the penetration of the epithelium may be detectedby an energy detector based on a fluorescence of the epithelial layerirradiated with the larger sized pulse.

In many embodiments, the adjustably sized beam is scanned and sized inaccordance with a pre-programmed sequence to vary the location and sizeof the beam.

In many embodiments, the adjustably sized beam repeatedly changes fromat least one smaller size to at least one larger size before thepenetration of the epithelium is detected so that the ablated layer ofepithelium is substantially uniform when the penetration of theepithelium is detected.

In many embodiments, the adjustably sized beam changes from at least onesmaller size to at least one larger size at least about three times, forexample five times, before the penetration of the epithelium isdetected. In some embodiments, the smaller beam size is no more thanabout 2.5 mm across and the larger size is at least about 3.5 mm across.In specific embodiments, the smaller size may be no more than about 1.75mm across and the larger size is at least 4 mm across.

In many embodiments, the adjustably sized beam changes from a smallersize to a larger size in correlation with an intended sub-layer ofepithelial tissue ablated. In some embodiments, the intended sub-layercorresponds to an upper portion of the epithelial layer, and theadjustably sized beam changes from the smaller size to the larger sizefor each additional sub-layer ablated with the adjustably sized laserbeam. In specific embodiments, a plurality of the additional sub-layersis ablated before the penetration of the epithelium is detected.

In many embodiments, the tissue fluorescence comprises auto-fluorescenceof the tissue that originates from excitation of the molecules of thetissue with the adjustably sized laser beam.

In many embodiments, the adjustably sized beam is sized to provide atleast one intermediate beam size having a cross sectional size betweenthe at least the smaller beam size and the larger beam size.

In many embodiments, the adjustably sized beam is repeatedly sized sothat the larger size comprises several beam sizes and the smaller sizecomprises several small beam sizes.

In another aspect, embodiments of the current invention provide a systemto ablate an eye to remove an epithelial layer of the eye. A lasergenerates a beam of an ablative radiation. A movable scan componentscans the laser beam over a region of the eye to ablate the epitheliallayer. A processor, which comprises a tangible medium and memory, iscoupled to the laser and the movable scan component. The processor isconfigured to scan the beam within the region in accordance with a pulsesequence arranged to enhance an optical feedback signal based on atissue fluorescence of the epithelial layer.

In many embodiments, the computer is configured to sort the pulsesequence to enhance the optical feedback.

In many embodiments, the system further comprises at least one lens toform an optical image of the fluorescence that is visible to an operatorsuch that the operator can detect the penetration of the epitheliallayer based on the optical feedback signal.

In another aspect, embodiments of the current invention provide a systemto ablate an eye to remove an epithelial layer of the eye. The systemcomprises a laser to generate a beam of ablative radiation. A movablestructure is disposed along the laser beam path to adjust a size of thelaser beam to at least one smaller size and at least one larger size. Amovable scan component is configured to scan the laser beam over aregion of the eye to ablate the epithelial layer. A processor, whichincludes tangible medium and memory, is coupled to the laser, themovable structure, and the movable scan component. The processor isconfigured to ablate an epithelium with at one larger beam size and atleast one smaller beam size so that a penetration of the epithelium canbe detected based on a tissue fluorescence from the larger size of thebeam during a procedure.

In many embodiments, the system comprises at least one of a display or amicroscope to provide an image of the tissue fluorescence to an operatorso that the operator can detect the penetration of the epithelium.

In some embodiments, the system may include an energy detector to detectthe penetration of the epithelium based on the fluorescence.

In many embodiments, the region of the eye comprises a central regionand an outer peripheral region. The processor is configured to overlapseveral pulses of at least one larger size of the beam in the centralregion to penetrate the epithelium in the central region. In someembodiments, the processor is configured to deliver the pulses with atleast one larger size beam to cover the central region to provide ameasurement signal from the central region. In specific embodiments, theprocessor can be configured to deliver pulses of the larger size beam(s)that cover the central region at a rate of at least about 1 Hertz todetect penetration of the epithelium from the measurement signal.

In many embodiments, the processor is configured to scan the laser beamover the region in accordance with a pre-programmed sequence to vary thesize and location of the beam. The processor may also be configured tovary between at least one smaller size and at least one larger size toablate the epithelium at substantially uniform rate. The processor mayalso be configured to vary the sized beam from at least one smaller sizeto at least one larger size in correlation with an intended sub-layer ofablated epithelial tissue.

In many embodiments, the small sized beam comprises a substantiallycircular beam with a diameter no more that about 2 mm across and thelarge sized beam is circular with a diameter at least about 4 mm across.

In many embodiments, the tissue fluorescence comprises anauto-fluorescence of the tissue that originates from excitation ofnaturally occurring molecules within tissue in which the molecules areexcited with the pulsed laser beam.

In many embodiments, the movable structure may comprise an irisdiaphragm, a plurality of apertures formed in a non-transmissivematerial or a lens.

In many embodiments, the movable scan component may comprise a movablemirror, a movable lens or a movable prism.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a laser ablation system forincorporating the invention;

FIG. 1A illustrates an ablation of an epithelial layer of an eye using aseries of scanning laser beam pulses of varying diameter applied over aregion of a cornea of an eye, according to embodiments of the presentinvention;

FIGS. 2 and 3 schematically illustrate a laser beam delivery system forselectively directing a laser beam onto the corneal tissue, according toembodiments of the present invention;

FIG. 4 is a function block diagram illustrating a control architectureof an ablation system as in FIG. 1;

FIG. 5A shows an epithelial ablation profile of an ablated region of anepithelial layer, according to embodiments of the present invention;

FIG. 5B shows a portion of a sequence of scanning laser beam pulses toused ablate the epithelial layer with the profile of FIG. 5A, in whichthe pulses are sized and positioned so as to permit detection of apenetration of the epithelial layer, according to embodiments of thepresent invention;

FIG. 5C shows penetration of the epithelial layer with a marker pulse ofthe sequence as in FIG. 5B, according to embodiments of the presentinvention;

FIG. 5D shows a display visible to a system operator in which theoperator can detect penetration of the epithelial layer with the pulsesof FIGS. 5B and 5C, according to the embodiments of the presentinvention;

FIG. 6A illustrates theoretical ablation profiles that can be attainedupon penetration of the epithelium, according to embodiments of thepresent invention;

FIG. 6B shows a timing diagram illustrating pulse count, approximateaverage ablation depth and adjusted laser beam diameter while the laserbeam pulses ablate tissue with profiles as in FIG. 6A, according toembodiments of the present invention;

FIG. 7A shows bulk ablation of a first portion of an epithelial layerand incremental step ablation of additional sub-layers of epithelialtissue, according to embodiments of the present invention;

FIG. 7B shows a timing diagram illustrating approximate average ablationdepth and adjusted laser beam diameter while the laser beam pulsesablate a first portion of the epithelial layer and additional sub-layersof epithelial tissue as in FIG. 7A, according to embodiments of thepresent invention;

FIG. 8 shows a method of epithelial ablation, according to embodimentsof the present invention; and

FIG. 9 shows a treatment table in accordance with an embodiment of thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is particularly useful for enhancing the accuracyand efficacy of laser eye surgical procedures, such as photorefractivekeratectomy (PRK), phototherapeutic keratectomy (PTK), and the like.Preferably, the present invention can provide enhanced optical accuracyof refractive procedures and improved patient comfort during theprocedure by improving removal of the corneal epithelium. Hence, whilethe system and methods of the present invention are described primarilyin the context of a laser eye surgery system for treating a cornea ofthe eye, it should be understood the techniques of the present inventionmay be adapted for use in alternative ablation procedures.

The techniques of the present invention can be readily adapted for usewith existing laser systems. By providing a more rapid (and hence, maybe less prone to error) methodology for correcting optical errors of aneye, the present invention facilitates sculpting of the cornea so thattreated eyes may regularly receive a desired optical correction havingimproved vision with minimal discomfort to a patient.

As used herein a substantially constant power level encompasses a powerlevel that is stable to within about 25% of an average power level.

Referring now to FIG. 1, a laser eye surgery system 10 for incorporatingthe present invention includes a laser 12 that produces a laser beam 14.Laser 12 is optically coupled to laser delivery optics 16, which directslaser beam 14 to an eye of patient P. A delivery optics supportstructure (not shown here for clarity) extends from a frame 18supporting laser 12. An input device 20 is used to align laser system 10with patient P. A microscope 21 is mounted on the delivery opticssupport structure, the microscope often being used to image a cornea ofeye E. The laser eye surgery system 10 may include a display 23 thatprovides an image of eye E that is visible to the user. A video camera25 can be optically coupled to microscope 21 to provide an image of theeye E on the display as seen through the microscope. Microscope 21 maycomprise at least one lens to form an optical image of the tissuefluorescence that is visible to the operator such that the operator candetect penetration of the epithelial layer based on the opticalfeedback. Although a microscope is shown, in some embodiments a cameralens can be used to image the tissue fluorescence, such that the imageof the tissue fluorescence can be shown on the display. In variousembodiments, the laser eye surgery system 10 includes at least someportions of a Star S3 Active Trak™ Excimer Laser System and/or a STAR S4IR™ Excimer Laser System with Variable Spot Scanning (VSS™) and WaveScanWaveFront® System available from VISX, INCORPORATED of Santa Clara,Calif.

While the input device 20 is here schematically illustrated as ajoystick, it should be understood that a variety of input mechanisms maybe used. Suitable input mechanisms may include trackballs, touchscreens, or a wide variety of alternative pointing devices. Stillfurther alternative input mechanisms include keypads, data transmissionmechanisms such as an Ethernet, intranet, internet, a modem, or thelike.

Laser 12 generally comprises an excimer laser, ideally comprising anargon-fluorine laser producing pulses of laser light having a wavelengthof approximately 193 nm. The pulse of laser light typically has a fixedpulse duration having a full width half maximum (FWHM) of about 15 nanoseconds during a treatment. Laser 12 will preferably be designed toprovide a feedback stabilized fluence at the patient's eye, deliveredvia delivery optics 16. The present invention may also be useful withalternative sources of ultraviolet or infrared radiation, particularlythose adapted to controllably ablate the corneal tissue without causingsignificant damage to adjacent and/or underlying tissues of the eye. Thelaser system may include, but is not limited to, excimer lasers such asargon-fluoride excimer lasers (producing laser energy with a wavelengthof about 193 nm), solid-state lasers, including frequency multipliedsolid-state lasers such as flash lamp and diode pumped solid-statelasers. Exemplary solid state lasers include UV solid state lasers(approximately 193-215 nm) such as those disclosed in U.S. Pat. Nos.5,144,630 and 5,742,626; Borsuztky et al., “Tunable UV Radiation atShort Wavelengths (188-240 nm) Generated by Sum Frequency Mixing inLithium Borate”, Appl. Phys. 61:529-532 (1995), and the like. The laserenergy may comprise a beam formed as a series of discreet laser pulses.A variety of alternative lasers might also be used. Hence, although anexcimer laser is the illustrative source of an ablating beam, otherlasers may be used in the present invention.

Laser 12 and delivery optics 16 will generally direct laser beam 14 tothe eye E of patient P under the direction of a computer 22. Computer 22will often selectively adjust laser beam 14 to expose portions of thecornea to the pulses of laser energy so as to effect a predeterminedsculpting of the cornea and alter the refractive characteristics of theeye. In many embodiments, both laser 14 and the laser delivery opticalsystem 16 will be under computer control of processor 22 to effect thedesired laser sculpting process, with the processor effecting (andoptionally modifying) the pattern of laser pulses. The pattern of pulsesmay by summarized in machine readable data of tangible media 29 in theform of a treatment table, and the treatment table may be adjustedaccording to feedback input into processor 22 from an automated imageanalysis system (manually input into the processor by a system operator)in response to feedback data provided from an ablation monitoring systemfeedback system. Such feedback might be provided by integrating thewavefront measurement system described below with the laser treatmentsystem 10, and processor 22 may continue and/or terminate a sculptingtreatment in response to the feedback, and may optionally also modifythe planned sculpting based at least in part on the feedback.

Laser beam 14 may be adjusted to produce the desired sculpting using avariety of alternative mechanisms. The laser beam 14 may be selectivelylimited using one or more variable apertures. An exemplary variableaperture system having a variable iris and a variable width slit isdescribed in U.S. Pat. No. 5,713,892, the full disclosure of which isincorporated herein by reference. The laser beam may also be tailored byvarying the size and offset of the laser spot from an axis of the eye,as described in U.S. Pat. No. 5,683,379, and as also described inco-pending U.S. patent application Ser. Nos. 08/968,380, filed Nov. 12,1997; and 09/274,999 filed Mar. 22, 1999, the full disclosures of whichare incorporated herein by reference.

Still further alternatives are possible, including scanning of the laserbeam over a surface of the eye and controlling the number of pulsesand/or dwell time at each location, as described, for example, by U.S.Pat. No. 4,665,913 (the full disclosure of which is incorporated hereinby reference); using masks in the optical path of laser beam 14 whichablate to vary the profile of the beam incident on the cornea, asdescribed in U.S. patent application Ser. No. 08/468,898, filed Jun. 6,1995 (the full disclosure of which is incorporated herein by reference);hybrid profile-scanning systems in which a variable size beam (typicallycontrolled by a variable width slit and/or variable diameter irisdiaphragm) is scanned across the cornea; or the like. The computerprograms and control methodology for these laser pattern tailoringtechniques are well described in the patent literature.

Additional components and subsystems may be included with laser system10, as should be understood by those of skill in the art. For example,spatial and/or temporal integrators may be included to control thedistribution of energy within the laser beam, as described in U.S. Pat.No. 5,646,791, the disclosure of which is incorporated herein byreference. An ablation effluent evacuator/filter, and other ancillarycomponents of the laser surgery system which are not necessary to anunderstanding of the invention, need not be described in detail for anunderstanding of the present invention.

Processor 22 may comprise (or interface with) a conventional PC systemincluding the standard operator interface devices such as a keyboard, adisplay monitor, and the like. Processor 22 will typically include aninput device such as a magnetic or optical disk drive, an internetconnection, or the like. Such input devices will often be used todownload a computer executable code from a tangible storage media 29embodying any of the methods of the present invention. Tangible storagemedia 29 may take the form of a floppy disk, an optical disk, a datatape, a volatile or non-volatile memory, or the like, and the processor22 will include the memory boards and other standard components ofmodern computer systems for storing and executing this code. Tangiblestorage media 29 may optionally embody wavefront sensor data, wavefrontgradients, a wavefront elevation map, a treatment map, a cornealtopography map, a measurement of refraction of the eye, and/or anablation table.

An ablation of an epithelial layer eye using a series of pulses 14 a-14e of a scanning laser beam is illustrated in FIG. 1A. The series ofpulses are applied over a trans-epithelial ablation region 15 of acornea C of an eye E. As illustrated in FIG. 1A pulses 14 e and 14 doverlap. A dimension across pulse 14 c is smaller than a dimensionacross pulse 14 b. The series of pulses 14 a to 14 e are sequentiallyapplied to eye E in accordance with a treatment table listing thecoordinates and sizes of the laser beam for each pulse. An additionalablation procedure can then be ablated into the stromal corneal tissueto provide a refractive correction. In some embodiments, the epitheliumcan be ablated to remove corneal haze.

Referring now to FIG. 2, laser beam delivery system 16 for directinglaser beam 14 at eye E will often include a number of mirrors 30, aswell as one or more temporal integrators 32 which may even (or otherwisetailor) the energy distribution across the laser beam. Laser 12 willoften comprise an excimer laser as described above.

In the exemplary embodiment, a variable aperture 34 changes a diameterand/or slot width to profile laser beam 14, ideally including both avariable diameter iris and a variable width slot. A prism 36 separateslaser beam 14 into a plurality of beamlets, which may partially overlapon eye E to smooth edges of the ablation or “crater” from each pulse ofthe laser beam. Referring now to FIGS. 2 and 3, an offset module 38includes motors 40 which vary an angular offset of an offset lens 42,and which also change the radial orientation of the offset. Hence,offset module 38 can selectively direct laser beam 14 at a desiredlateral region of the cornea. A structure and method for using laserbeam delivery system 16 and offset module 38 are more fully described inU.S. Pat. Nos. 6,984,227; 6,331,177; 6,203,539; 5,912,775; and 5,646,791the full disclosures of which are incorporated herein by reference.

Referring now to FIG. 4, a control system of a laser system 10 isschematically illustrated according to the principles of the presentinvention. A processor 22 enables precise control of laser system 10 tosculpt a surface shape specified in a laser treatment table 52. Aprocessor 22, which generally comprises a PC workstation, makes use of acomputer program stored on a tangible media 29 to generate treatmenttable 52. Processor 22 includes a library 44 of treatments and treatmenttables as described in U.S. Pat. Nos. 6,245,059; and 7,077,838, the fulldisclosures of which are incorporated herein by reference. An embeddedcomputer 58 within laser system 10 is in electronic communication withthe PC workstation. Alternatively, a PC workstation may be embedded inthe laser system and include an embedded processor card in communicationwith the PC workstation for directing the ophthalmic surgery.

Embedded computer 58 is in electronic communication with a plurality ofsensors 56 and a plurality of motor drivers 60. The motor drivers 60 arecoupled to the embedded computer 58 to vary the position andconfiguration of many of the optical components of the delivery optics16 according to treatment table 52. For example, first and secondscanning axis 62, 64 control the position of the offset lens to move thebeamlets over the surface of the cornea. Iris motor 66 controls thediameter of the overall beam, and in some cases, the length of lighttransmitted through a variable width slot. Similarly slot width driver68 controls the width of the variable slot. Slot angle driver 70controls rotation of the slot about its axis. Beam angle driver 72controls rotation of the beam as effected by a temporal integrator asdescribed above. Processor 22 issues a command for laser 12 to generatea pulse of the laser beam 14 after the various optical elements havebeen positioned to create a desired crater on eye E. Treatment table 52comprises a listing of all of the desired craters to be combined so asto effect a treatment therapy.

A timer 80 is located on an add on card of processor 22 and is aLab-PC-1200 model card having timers 8253/8254. The Lab-PC-1200 modelcard is available from National Instruments of Austin, Tex. In alternateembodiments, timer 50 is located externally to processor 22. The timer80 is controlled by a computer program of processor 22 and is adapted tomeasure time intervals. The laser 12 is electronically coupled toprocessor 22. Laser 12 fires upon a command issued from processor 22 inresponse to a time interval measured by timer 80. Processor 22 variesthe rate at which laser 62 fires during at least a portion of atreatment of an eye E.

FIG. 5A shows an ablation profile 107 of an ablation region 100 of anepithelial layer, according to embodiments of the present invention.Cornea C includes an epithelial layer 102 and a stromal layer 104. ABowman's membrane 103 is disposed between epithelial layer 102 andstromal layer 104. Ablation profile 107 can include a clearance region106 in which the epithelium is removed, and a transition zone 108 whichextends from clearance region 106 to the unablated regions of thecornea. Transition zone 108 can be annular and extend with a spline,linear fit, or other connecting shape between the unablated epitheliumand clearance region 106. Examples of shapes that can be used astransition zones are described in U.S. patent application Ser. No.10/100,231, filed Mar. 14, 2002, published as US 2003/0176855, the fulldisclosure of which is incorporated herein by reference. Clearanceregion 106 can include a diameter across 106D. Ablation profile 107 ofablation region 100 includes transition zone 108 and can include adiameter 107D across ablated region 107. The laser can be programmed toablate the epithelial layer with a series of laser beam pulses in manyways, for example as described in U.S. Pat. No. 7,008,415, the fulldisclosure of which is incorporated herein by reference.

The characteristics of epithelial ablation profile 107 can be selectedand/or adjusted by the operator as desired, and input with a treatmentscreen shown on a display as described above. Clearance region 107 canbe selected and/or adjusted to many values, for example values fromabout 8.0 to about 9.5 mm. The maximum ablation zone can be about 2 mmgreater than the selected clearance zone to provide an annulartransition zone about 1 mm thick. In many embodiments, the width of theannular transition zone as defined from an inner circumference to anouter circumference can be selected to be from about 0.75 to 1.5 mm,although narrower sized transition zones may require addition smalllaser beam pulses, thereby potentially increasing treatment time. Largersized transition zones may provide faster tissue removal with largerpulses, although in some embodiments a larger transition zone can causethe ablation to encroach on the limbus. In some embodiments, the maximumablation width can be limited to about 12 mm. Alternatively oradditionally, the maximum ablation width can be based on physiologicmeasurements from a wavefront machine, topography machine, or theoperating microscope, such that the maximum ablation width is 1 mm lessthan the diameter of the limbus. The maximum depth of ablation can beabout 75 microns. The thickness of the epithelial layer can be thickerperipherally than centrally such that the epithelium has a meniscusshape and the operator and/or ablation algorithm can compensate for athicker peripheral epithelium. The thickness and optical power of theepithelium may also be related to the curvature of the cornea. Thecurvature of the cornea can be measured with a keratometer and/ortopography machine and the keratometer values can be input by theoperator and incorporated into the ablation algorithm.

FIG. 5B shows a portion of a sequence 120 of scanning laser beam pulsesto used ablate the epithelial layer with the profile of FIG. 5A, inwhich the pulses are sized and positioned so as to permit detection of apenetration of the epithelial layer, according to embodiments of thepresent invention. Although circular pulses are shown, many pulsegeometries can be used, for example a variable width slit and/orvariable diameter iris diaphragm, and the size of the pulse can refer toa dimension across the pulse, for example a dimension across a slit.Sequence 120 of scanning laser beam pulses can be applied to ablationregion 100. Ablation region 100 can include a center 112. Sequence 120includes individual laser beam pulses 120A to 120G. Laser beam pulses120A to 120G are sized and positioned in ablation region 100 accordingto a treatment table. A cross sectional size of each of pulses 120A to120G can refer to a cross sectional diameter of each of the pulses andposition of laser beam pulses 120A to 120G can refer to a position of acenter of each pulse in relation to center 112 of ablated region 100.Laser beam pulses 120A to 120D have a small cross sectional size, forexample less than about 2 mm. Laser beam pulses 120E to 120G have alarge cross sectional size, for example larger than about 3.5 mm. Thesequence of laser beam pulses can include additional sizes of laser beampulses, for example intermediate size pulses having a diameter greaterthan about 2 mm and less than about 3.5 mm. Laser beam pulses 120E to120G overlap and cover a central region 110.

Fluorescence from central region 110 can be monitored to detectpenetration of the epithelial layer. In many embodiments, thefluorescence that is monitored can comprise tissue auto-fluorescencethat results from native molecules of the epithelial layer that areexcited with the ablative laser radiation. In some embodiments, thefluorescence can include fluorescence that results from the excitationof a fluorescent dye applied to the epithelium, which fluoresces inresponse to excitation from the ablative laser radiation. Althoughoverlap is shown in the central region, the pulse sequence can bearranged to overlap and cover other locations of the ablation region,for example peripheral regions, such that optical feedback is enhancedin the peripheral regions where the pulses overlap.

The small size laser beam pulses can include several sizes of laser beampulses, and the large and intermediate size laser beam pulses can alsoinclude several sizes of laser beam pulses. For example, in manytreatments the small sized laser beam pulses will comprises severalpulses having a diameter from about 0.7 mm to about 2.5 mm, and thelarge size laser beam pulses will comprise several laser beam pulseshaving a diameter from about 3.5 to about 6.5 mm. In many embodiments,the laser beam pulses used to ablate the epithelial layer can includeseveral intermediate sized laser beam pulses having a diameter fromabout 2.5 to 3.5 mm. Small size laser beam pulses can be used to provideaccurate ablation of tissue and minimize residual error while medium andlarge pulses can provide faster tissue removal and permit the user tovisualize penetration of the epithelium. In preferred embodiments, smallpulses may be used initially followed by large pulses, although thepulse sequence can be sorted in many ways. In some embodiments, a laserbeam pulse with a particular size can include several simultaneouslygenerated overlapping laser beams, for example as described in U.S. Pat.No. 6,984,227, previously incorporated herein by reference.

The pulse sequence can be arranged to provide medium to large sizedlaser beam pulses that overlap in central region 110 to mark thepenetration of the epithelium based on a decrease in fluorescence uponpenetration of the epithelium. Auto-fluorescence of the epithelial layeris greater than the auto-fluorescence of the underlying stromal layer sothat the pulses in central region 110 appear bright initially due toauto-fluorescence of the epithelial layer. Upon penetration into thestromal layer and many instances upon penetration into Bowman'smembrane, the auto-fluorescence decreases rapidly so that penetration ofthe epithelium can be detected. In some embodiments, large laser beampulses can cover central region 110 so as to permit detection of thepenetration of the epithelium. Each of pulses 120E to 120G are sizedwith a diameter and positioned in ablated region 100 so that each ofpulses 120E to 120G covers central region 110. Thus, an operator viewingthe ablation of region 100 can detect penetration of the epitheliumvisually by observing central region 110 and monitoring the tissuefluorescence of central region 110 that results from the marker pulsesapplied to ablated region 100. In a preferred embodiment central region110 has a dimension across of about 3 mm, although central region 110can be from about 2 to 6 mm across. Also, although central region 110 isshown as circular, central region 110 can be hexagonal, triangular nornearly any other shape that can provide a central region in which thefluorescence pattern appears substantially uniform until the epitheliumis penetrated. In some embodiments, marker pulses can be applied tonon-central regions of the ablation region, for example to peripheralregions, such that penetration of the epithelium can be detectedperipherally with the marker pulses overlapping in the periphery of theablated region.

The use of large to medium size pulses to mark the penetration of theepithelium can be accomplished in any number of ways. Work in relationwith embodiments the present invention suggests that medium to largepulses applied to central region 110 with a frequency of at least about0.5 Hz can provide a sufficient visual stimulus for an operator todetect penetration of the epithelial layer based on tissueauto-fluorescence in the visible portion of the spectrum ofelectromagnetic radiation. The marker pulses can be repeated at manyfrequencies from about 0.5 Hz to about 50 Hz, so that an operator canreadily detect penetration of the epithelium based on theauto-fluorescence of the epithelium originating from the central regionwith the marker pulses. For example, in many embodiments, the markerpulses are repeated at a frequency of about 5 to 20 Hz. In preferredembodiments, about two to three marker pulses can be appliedsequentially at about 20 Hz and about 1 second later an additional twoto three marker pulses can be applied at about 20 Hz. Thus, the operatorcan readily visualize a penetrated region of the epithelium with markerpulses spaced no more than one second apart and applied with a frequencyof at least about 1 Hz. In many embodiments, large central marker pulsescan comprise at least about 5% of the total number of pulses used toablate the epithelium for example from 5 to 25% of the total number ofpulses delivered during ablation of the epithelium. In many embodiments,the large central marker pulses comprise at least about 10% of the totalnumber of pulses used to ablate the epithelium, for example from about10 to 15% of the total number of pulses applied to ablated theepithelium.

FIG. 5C shows penetration of the epithelial layer with a marker pulse ofthe sequence as in FIG. 5B, according to embodiments of the presentinvention. Central region 110 is covered by pulse 120E. An epithelialfluorescence pattern 130A indicates where the epithelium has not beenpenetrated. A stromal and/or Bowman's fluorescence pattern 130Bindicates where the epithelium has been penetrated. Subsequent pulses120F and 120G cover central region 110 so that stromal and/or Bowman'sfluorescence pattern 130B has substantially the same shape and becomessomewhat larger. Because stromal and/or Bowman's fluorescence pattern130B has substantially the same shape with sequential pulses, stromaland/or Bowman's fluorescence pattern can be readily identified with themarker pulses to detect penetration of the epithelium. Prior topenetration of the epithelium, central region 110 has a substantiallyuniform fluorescence intensity which provides a substantially uniformfluorescence pattern within central region 110. Thus, an operator canreadily visualize the penetration of the epithelium based on the changein tissue fluorescence within central region 110.

FIG. 5D shows an optical image 140 of the eye with a fluorescencepattern that is visible to a system operator in which the operator candetect penetration of the epithelial layer with the pulses of FIGS. 5Band 5C, according to the embodiments of the present invention. Opticalimage 140 can be displayed on a computer display as described above. Inmany embodiments, optical image 140 can be seen by the operator throughan operating microscope as described above. Optical image 140 caninclude a reticule 142 for alignment of the ablation. Reticule 142 caninclude concentric circles 144A to 144C. In a preferred embodiment,reticule 144C corresponds to central region 110. The operator observesepithelial fluorescence 130A and can detect penetration of theepithelium based on the appearance of stromal and/or Bowman's ablationpattern 130B. In some embodiments, a detector, for example a CCD thatdetects optical image 140, can be used with the pulse sequences andoptical system as described herein to automate detection of theepithelial penetration and generate an automated optical feedbackcontrol signal in response to the penetration of the epithelium. Inthese embodiments, the detector that detects optical image 140 has aview of eye E. The sorted pulse sequences and optical feedback asdescribed herein can be incorporated into systems that automaticallydetect penetration of the epithelium to provide control signals, forexample as described in U.S. Pat. Nos. 6,293,939; 6,019,755; and5,505,724; the full disclosures of which are incorporated by reference.

The operator can respond to the visual optical feedback signal in manyways. For example, the operator can terminate the ablation of theepithelium and proceed to ablate the stroma with a desired opticaland/or therapeutic correction. The ablation of the stroma can comprisean optical correction such as a wavefront ablation and/or a therapeuticablation such as the removal of corneal haze. In many embodiments, priorto stromal ablation and after detection of epithelial penetration, theoperator may respond to the detection of epithelial penetration byscraping the exposed surface to ensure that all epithelial material hasbeen removed so that any debris that may be present does not effect thestromal ablation process.

In embodiments where epithelial penetration is not detected with a firstsequence of pulses, the operator may respond to the optical feed backsignal by selecting additional pulses and/or sequence(s) to ablateadditional sub-layers of the epithelium. In some embodiments, forexample, once a first sequence of pulses corresponding to first ablationdepth, for example 50 um, has been applied, the optical feedback signalmay indicate that the epithelium has not been penetrated. In response,the operator may select ablation with an additional sequence of pulsescorresponding to ablation of an additional layer of epithelial tissue,for example 5 um, and ablate this additional layer of tissue whileobserving the ablation process optical feedback provided by the sortedpulses. This process can be repeated with additional sequences thatcorrespond to the ablation of additional layers, for example in 5 umincrements, until penetration is detected in the central region or atotal maximum allowed ablation depth, for example 70 um, has beenachieved. The first ablation depth corresponding to the first sequencecan be from about 30 to about 60 microns, for example 50 um as describedabove. The additional ablation depth(s) corresponding to the additionalsequence(s) can correspond to depths for each layer within a range fromabout 1 to about 10 microns, for example 5 um as described above. Theabove pulses sequences can be sorted to enhance optical feedback asdescribed above.

FIG. 6A illustrates ablation profiles that can be attained uponpenetration of the epithelium, according to embodiments of the presentinvention. Upon detection of penetration of the epithelium, the operatorcan stop the laser ablation of the epithelial surface. Thus, it isdesirable that the ablated layer of epithelial tissue is smooth when theoperator terminates the ablation of the epithelial surface. Ablationprofile 150A shows a theoretical ablation profile that results from theoperator stopping the epithelial ablation when the epithelium ispenetrated at an average ablation depth of 30 microns. Ablation profile150B and ablation profile 150C show theoretical ablation profiles forepithelial ablations terminated at average ablation depths of 50 micronsand 70 microns respectively. Similar ablation profiles can be achievedfor ablations terminated at many depths between 30 and 70 microns.

The ablation algorithm can be designed to provide a sequence of pulseswhich provide a desired amount of smoothness, based on the purpose ofthe underlying stromal ablation. Ablation profiles 150A to 150C show asmooth central region that extends about 6 mm across from a radialposition of about −3 mm to a radial position of about +3 mm. The smoothcentral region corresponds to the ablated optical zone in which stromaltissue is ablated with a refractive optical correction. The smoothnessof the ablated epithelial shape can have an RMS value of about 3 um orless, for example 2 um, and a peak to valley roughness of about 10 um orless, 5 um or less. The rougher peripheral region corresponds to theablated transition zone as described above. As the transition zone isablated may not be used to provide optical correction of stromal tissue,the exactness of the epithelial ablation over the transition zone may beless critical. In some embodiments, the roughness of the ablatedtransition zone can have a peak to valley roughness of 20 um or less,for example 10 um or less. As the operator may interrupt the ablation atany time, the smoothness of an ablation that is interrupted in responseto penetration of the epithelium may be slightly rougher. To minimizethe roughness of ablations that are terminated upon penetration of theepithelium, the pulses are arranged accordingly to provide a smoothablation upon termination. Work in relation with embodiments of thepresent invention indicates that ablations terminated in response todetection of epithelial penetration can provide smooth surfaces, forexample ablation surface having roughness metrics approximately twicethose described for ablation to a predetermined depth.

FIG. 6B shows a timing diagram illustrating pulse count, approximateaverage ablation depth and adjusted laser beam diameter while the laserbeam pulses ablate tissue with profiles as in FIG. 6A, according toembodiments of the present invention. The timing diagram includes atreatment time 162 in seconds, a pulse number 164, an approximateaverage ablation depth 166, and an adjusted beam diameter 168 used toablate epithelial tissue.

For a laser with a nearly constant laser pulse firing rate, for example20 Hz, pulse number 164 is closely correlated with treatment time 162.Although pulse number 164 increases linearly with time, in manyembodiments it may be desirable to very the laser pulse firing rate bycontrolling a time delay between each pulse. The average depth ofablation is related to the treatment time and increases with increasingtreatment time. In general, the average depth of ablation proceeds at arate of about 1 micron per second, although slower rates can beclinically effective and acceptable.

A vertical line 169 shows adjusted beam diameter 168 for several pulses.As will be appreciated with reference to pulse number 164 and verticalline 169, vertical line 169 indicates the size of the laser beam forseveral pulses of the laser beam, for example about 20 pulses of thelaser beam from the 400th pulse to the 420th pulse of the sequence.Thus, each vertical line that corresponds to adjusted beam diameter 168represents several laser beam pulses of the same diameter, and theselaser beam pulses of the same diameter can be scanned to differentlocations over the ablation region in accordance with the coordinatereferences of the treatment table.

Adjusted laser beam diameter 168 varies during the ablation of theepithelium. Adjusted laser beam diameter 168 includes several diametersused to ablate the first 30 microns of tissue and these diameters areindicated by arrow 160A. As the epithelial tissue layer is usually noless than 30 microns thick, laser beam pulses of increasing diameter areused to ablate the first 30 microns of tissue. If the operatorterminates the ablation at a depth of 30 microns ablation profile 150Awill be smooth as shown above.

Adjusted laser beam diameter 168 includes several diameters used toablate epithelial tissue from an average depth of 30 microns to anaverage depth of 70 microns are indicated by arrow 160B and arrow 160C.As the epithelial tissue layer can be from 30 to 70 microns thick, laserbeam pulses of alternating and/or interleaved large and small sizes canbe used to ablate the epithelial tissue layer from 30 microns to 70microns. Arrow 160B shows beam sizes for ablation from a depth of 30 to50 microns, and arrow 160C shows ablation from a depth of 50 to 70microns. From 30 to 50 microns, large diameter marker pulses 170A areapplied to detect penetration of the epithelium, and small diameterpulses 170B are applied between marker pulses 170A to ensure that theablation profile is smooth when the operator terminates ablation of theepithelium at a depth based on the detected penetration. From 50 to 70microns, large diameter marker pulses 170C are applied to detectpenetration of the epithelium, and small diameter pulses 170D areapplied between marker pulses 170C to ensure that the ablation profileis smooth when the operator terminates ablation of the epithelium at adepth based on the detected penetration. If the operator terminates theablation at any average ablation depth from 30 microns to 70 microns,the ablation profile will be smooth as shown above. Large beam sizes areused to remove tissue rapidly and provide marker pulses as describedabove, and the small beam pulses are interleaved between the markerpulses to knock down any non-uniformities in the ablation pattern thatdevelop as the ablation proceeds.

FIG. 7A shows bulk ablation of a first portion 210 of an epitheliallayer and incremental step ablation of additional sub-layers 220A to220C of epithelial tissue, according to embodiments of the presentinvention. First portion 210 of the ablated epithelial tissue can have adepth of approximately 50 microns, which corresponds to a typicalthickness of the ablated epithelial layer. In some embodiments, theoperator can program the bulk portion to have a selectable depth in arange from about 20 to 70 microns, for example from about 25 to 60microns. Additional sub-layers 220A to 220C can be sequentially ablated.Additional sub-layers 222 can be ablated as needed until penetration ofthe epithelium is detected. Each additional sub-layer has a thickness ofapproximately 1 to 10 microns, for example about 5 microns. Uponcompletion of ablation of the bulk layer sequence, the operator canprogram the laser to ablate an additional sub-layer if penetration isnot detected with ablation by the bulk sequence.

FIG. 7B shows a timing diagram illustrating approximate average ablationdepth and adjusted laser beam diameter while the laser beam pulsesablate a first portion of the epithelial layer and additional sub-layersof epithelial tissue as in FIG. 7A, according to embodiments of thepresent invention. The timing diagram includes a treatment time 262 inseconds and an adjusted beam diameter 268 used to ablate epithelialtissue. Adjusted laser beam diameter 268 varies during the ablation ofthe epithelium. Adjusted laser beam diameter 268 includes severaldiameters used to ablate first portion 210 and these diameters areindicated by arrow 230. As the epithelial tissue layer is usually noless than 30 microns thick, first portion 210 often corresponds to anablation depth of 30 microns, and laser beam pulses of increasingdiameter are used to ablate first portion 210. When the operatorterminates the ablation, the ablation profile will be smooth as shownabove. In some embodiments, when an operator terminates the ablationduring ablation of a sub-layer of the epithelium, the laser may continuethe ablation until the ablation of the sub-layer is completed so thatthe ablation is uniform. Thus, it may be desirable to make thesub-layers thin so that the ablation of the entire sub-layer provides anacceptably thin ablation of the underlying stromal tissue and/orBowman's membrane.

Adjusted laser beam diameter 268 includes several diameters used toablated sub-layers 220A to 220C. As the epithelial tissue layer can befrom 30 to 70 microns thick, laser beam pulses of alternating and/orinterleaved large and small sizes can be used to ablate each of theepithelial tissue sub-layers 220A to 220C. Large diameter marker pulses270A can be applied to detect penetration of the epithelium, and smalldiameter pulses 270B can be applied between marker pulses 270B to ensurethat the ablation profile is smooth when the operator terminatesablation based on the detected penetration of the epithelial layer. Anarrow 242 indicates ablation of epithelial tissue with additionalsub-layers 222 at depths below those of sub-layers 220A to 220C. Largeand small pulses can be used to ablate each additional sub-layer so thatthe ablation is smooth when the operator terminates the epithelialablation in response to penetration of the epithelium.

It should be noted that although FIGS. 5B to 7B make reference toembodiments in which laser beams of varying size are used to ablate theepithelium, embodiments of the present invention can employ a fixeddiameter treatment beam to ablate the epithelium. Such embodiments canbe readily implemented on the VISX Star™ platform by constraining thetreatment table to provide a single fixed constant diameter laser beamduring the ablation of the epithelial. The treatment table can be sortedto provide enhanced optical feedback in the central region of theepithelial ablation. This sorting of predetermined fixed diameter laserbeam sequences can also be incorporated into laser systems such as thosedescribed in U.S. Pat. Nos. 6,635,051; 6,575,962; 6,090,110; and5,827,264, the full disclosures of which are incorporated herein byreference. Although these embodiments that employ a constant size laserbeam are within the scope and spirit of the present invention, work inrelation with the present invention suggests that the variable beamembodiments described herein can provide faster ablations with improvedoptical feedback and improved ablation characteristics, for examplesmoother ablation surfaces with well defined transition zones and welldefined ablation boundaries. In addition or in combination, it should benoted that solid state lasers can also be used to provide sortedablation sequences with improved optical feedback.

FIG. 8 shows a method of epithelial ablation 300, according toembodiments of the present invention. A step 310 selects laserepithelial removal and treatment parameters. Example parameters includea clearance zone diameter, a total ablation diameter, and a bulkablation depth, for example 50 microns. A step 320 applies a bulkablation sequence of laser beam pulses. A step 330 terminates and/orpauses ablation of the epithelial layer in response to detection ofpenetration of the epithelial layer and/or in response to completion ofthe bulk ablation sequence so that the epithelium has been uniformlyablated to the selected bulk ablation depth. If necessary, a step 360selects an additional step ablation sequence, for example a sequencethat ablates a 5 micron sub-layer of epithelial tissue. Step 330terminates and/or pauses ablation of the epithelium in response todetection of penetration of the epithelial layer and/or completion ofthe additional sub-layer ablated. Additional step sequences can beselected with step 360 and the ablation can be terminated and/or pausedat step 330 as many times as needed to detect penetration of theepithelium and/or a maximum ablation depth, for example 70 um

It should be appreciated that the specific steps illustrated in FIG. 8provide a particular method of measuring flow characteristics of a freestream according to an embodiment of the present invention. Othersequences of steps may also be performed according to alternativeembodiments. For example, alternative embodiments of the presentinvention may perform the steps outlined above in a different order.Moreover, the individual steps illustrated in FIG. 8 may includemultiple sub-steps that may be performed in various sequences asappropriate to the individual step. Furthermore, additional steps may beadded or removed depending on the particular applications. One ofordinary skill in the art would recognize many variations,modifications, and alternatives.

FIG. 9 shows a treatment table 900 in accordance with an embodiment ofthe present invention. Treatment table 900 includes several parametersto control the pulse size, location and delay for each pulse of thelaser beam. A pulse number 910 indicates the pulse number of thesequence. An estimated depth 920 corresponds to the estimated averageablation depth for each pulse number. An iris diameter 930 indicatesthat diameter of the laser beam on the eye for each pulse of the laserbeam. An x-coordinate 940 lists the x-coordinate location on the centerof the sized laser beam on the eye for each pulse of the laser beam. Ay-coordinate 950 lists the y-coordinate of the center of the sized laserbeam on the eye for each pulse of the laser beam. A delay 960 lists thedelay from the previous pulse for each pulse of the laser beam, so thatthe laser pulse repetition rate can be controlled for each pulse of thelaser beam. For example delay 960 listed as 50 ms corresponds to a laserfiring rate of 20 Hz, and delay 960 listed as 100 ms corresponds to alaser firing rate of 10 Hz. Appendix A, incorporated herein byreference, lists the entire treatment table 900 to an average ablationdepth of about 63 microns for about 1100 pulses.

While the present invention has been described with respect toparticular embodiments and specific examples thereof, it should beunderstood that other embodiments may fall within the spirit and scopeof the invention. The scope of the invention should, therefore, bedetermined with reference to the appended claims along with their fullscope of equivalents.

1. A method for removing an epithelial layer disposed over a stromallayer in a cornea, the method comprising: irradiating a region of theepithelial layer with laser ablation beam pulses of an ablativeradiation to ablate the epithelial layer; scanning the ablativeradiation to vary a location of the ablation beam pulses within theregion; adjusting the ablation beam pulses to include at least onesmaller sized ablation beam pulse and at least one larger sized ablationbeam pulse while the ablation beam pulses are scanned over the region inaccordance with an ablation beam pulse sequence, wherein the ablationbeam pulse sequence is sorted arranged to enhance optical feedback; anddetecting a penetration of the epithelial layer based on a tissuefluorescence from the at least one larger sized ablation beam pulse. 2.The method of claim 1 wherein the irradiated region has a central regionand an outer peripheral region and wherein the adjustably sized beampulse is sized and scanned so that several larger sized pulses comprisemarker pulses that overlap in the central region such that thepenetration of the epithelium is detected based on a decrease influorescence of the central region from the marker pulses.
 3. The methodof claim 2 wherein each of the marker pulses covers the central regionto provide a measurement signal from the central region.
 4. The methodof claim 3 wherein a distance across the central region is about 3 mmand each marker pulses is at least about 3.5 mm across so that eachmarker pulse overlaps and covers the central region.
 5. The method ofclaim 3 wherein the marker pulses that cover the central region aredelivered at a rate of at least about 1 Hertz to detect penetration ofthe epithelium.
 6. The method of claim 1 wherein the at least one largersized beam pulse has a distance across of at least about 3.5 mm and theat least one smaller sized beam pulse has a distance across of no morethan about 2.5 mm.
 7. The method of claim 6 wherein a distance acrossthe region is at least about 8 mm.
 8. The method of claim 6 whereinpulses of the at least one larger sized beam pulse comprise at leastabout 10% of a total number of pulses delivered before the penetrationis detected.
 9. The method of claim 1 wherein the penetration of theepithelium is detected by an operator based on a visible fluorescence ofthe epithelial layer irradiated with the at least one larger sized beampulse.
 10. The method of claim 1 wherein a penetration of the epitheliumis detected by an energy detector based on a fluorescence of theepithelial layer irradiated with the at least one larger sized beampulse.
 11. The method of claim 1 wherein the adjustably sized beam pulseis scanned and sized in accordance with a pre-programmed sequence tovary the location and size of the adjustably sized beam pulse.
 12. Themethod of claim 1 wherein the adjustably sized beam pulse repeatedlychanges from the at least one smaller sized beam pulse to the at leastone larger sized beam pulse before the penetration of the epithelium isdetected so that an ablated layer of epithelium is substantially uniformwhen the penetration of the epithelium is detected.
 13. The method ofclaim 12 wherein the adjustably sized beam pulse changes from the atleast one smaller sized beam pulse to the at least one larger sized beampulse at least about three times before the penetration of theepithelium is detected.
 14. The method of claim 13 wherein the at leastone smaller sized beam pulse comprises at least one beam size that is nomore than about 2.5 mm across and the at least one larger sized beampulse comprises at least one beam size at least about 3.5 mm across. 15.The method of claim 1 wherein the adjustably sized beam pulse changesfrom the at least one smaller sized beam pulse to the at least onelarger sized beam pulse in correlation with an intended sub-layer ofepithelial tissue ablated.
 16. The method of claim 15 wherein theintended sub-layer corresponds to an upper portion of the epitheliallayer, and the adjustably sized beam pulse changes from the at least onesmaller sized beam pulse to the at least one larger sized beam pulse foreach additional sub-layer ablated with the adjustably sized beam pulse.17. The method of claim 16 wherein a plurality of the additionalsub-layers is ablated before the penetration of the epithelium isdetected.
 18. The method of claim 1 wherein the tissue fluorescencecomprises an auto-fluorescence of the tissue that originates fromexcitation of the molecules of the tissue with the adjustably sized beampulse.
 19. The method of claim 1 wherein the adjustably sized beam pulseis sized to provide at least one intermediate sized beam pulse having across sectional size between the at least one smaller sized beam pulseand the at least one larger sized beam pulse.
 20. The method of claim 1wherein the adjustably sized beam pulse is repeatedly sized so that theat least one larger sized beam pulse comprises several beam sizes andthe at least one smaller sized beam pulse comprises several small beamsizes.
 21. A system to ablate an eye to remove an epithelial layer ofthe eye, the system comprising: a laser to generate an ablation beam ofan ablative radiation; a movable structure disposed along a path of thelaser beam to adjust a size of the laser ablation beam to at least onesmaller ablation size and at least one larger ablation size; a movablescan component configured to scan the adjustably sized laser ablationbeam over a region of the eye to ablate the epithelial layer; and aprocessor comprising a tangible medium and a memory, the processorcoupled to the laser, the movable structure and the movable scancomponent, the processor configured to ablate an epithelium with thelaser ablation beam while adjusted to the at least one larger ablationsize and the at least one smaller ablation size, wherein the processorsystem is configured to sort an arrangement of the at least one largerablation size and the at least one smaller ablation size to enhanceoptical feedback so that a penetration of the epithelium by the laserablation beam is detectable based on a tissue fluorescence of the eyefrom the at least one larger ablation size of the beam during aprocedure.
 22. The system of claim 21 further comprising at least one ofa display or a microscope to provide an image of the tissue fluorescenceto an operator so that the operator can detect the penetration of theepithelium.
 23. The system of claim 21 further comprising an energydetector to detect the penetration of the epithelium based on thefluorescence.
 24. The system of claim 21 wherein the region comprises acentral region and an outer peripheral region and the processor isconfigured to overlap several pulses of the at least one larger size ofthe beam in the central region to penetrate the epithelium in thecentral region.
 25. The system of claim 24 wherein the processor isconfigured to deliver the pulses with the at least one larger size beamto cover the central region to provide a measurement signal from thecentral region.
 26. The system of claim 25 wherein the processor isconfigured to deliver pulses of the at least one larger size beam thatcover the central region at a rate of at least about 1 Hertz to detectpenetration of the epithelium from the measurement signal.
 27. Thesystem of claim 21 wherein the processor is configured scan the laserbeam over the region in accordance with a pre-programmed sequence tovary the size and location of the beam.
 28. The system of claim 21wherein the processor is configured vary the size of the laser beambetween the at least one smaller size and the at least one larger sizeto ablate the epithelium at a substantially uniform rate.
 29. The systemof claim 21 wherein the processor is configured to vary the size of thelaser beam from the at least one smaller size to the at least one largersize in correlation with an intended sub-layer of epithelial tissueablated.
 30. The system of claim 21 wherein the at least one smallersize comprises a substantially circular cross-section with a diameter nomore than about 2 mm across and the at least one larger size comprises asubstantially circular cross-section with a diameter at least about 4 mmacross.
 31. The system of claim 21 wherein the tissue fluorescencecomprises an auto-fluorescence of a tissue of the eye that originatesfrom an excitation of naturally occurring molecules within the tissue inwhich the molecules are excited with the laser beam.
 32. The system ofclaim 21 wherein the movable structure comprises at least one of an irisdiaphragm, a plurality of apertures formed in a non-transmissivematerial or a lens.
 33. The system of claim 21 wherein the movable scancomponent comprises at least one of a movable mirror, a movable lens ora movable prism.